The A3 adenosine receptor (A3AR) belongs to the Gi-protein-associated cell membrane receptors. Activation of these receptors inhibits adenylate cyclase activity, inhibiting cAMP formation, leading to the inhibition of PKA expression and initiation of a number of downstream signaling pathways [1]. A variety of agonists to this receptor subtype have been synthesized, with IB-MECA (N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide) and its chlorinated form CI-IB-MECA (2-chloro-N6-(3-iodobenzyl)-adenosine-5′-N-methyluronamide), believed to be among the most potent and specific presently known A3AR agonists [2, 3]. Such compounds have shown efficacy in several animal models of inflammation, ischemia, reperfusion injuries, and cancer [1] and have advanced to clinical trial studies for rheumatoid arthritis and cancer.
Subjects with breast cancer, lung cancer, cervical cancer, ovarian cancer, germ cell tumors, acute leukemias and multiple myeloma who receive taxanes, platinum agents, vinca alkaloids and/or bortezomib as part of their initial therapy are at high risk of developing painful chemotherapy-induced peripheral neuropathy (CIPN) which can prematurely limit therapy and adversely impact quality of life. Thus, CIPN is a very serious complication of cancer chemotherapy and a major public health concern. It is estimated that the incidence of CIPN is as high as 70-90% in subjects receiving vincristine, cisplatin, oxaliplatin, and paclitaxel; 60% in subjects receiving docetaxel; 36-55% in subjects receiving bortezomib; and 40% in subjects receiving carboplatin [4, 5]. The development of CIPN with these agents appears not to be based on one single mechanism, as each of these drug classes possesses distinct anti-tumor mechanism of action [6]. There are currently no target-directed therapeutic approaches to treat CIPN. Consider the case of paclitaxel (Taxol®): Paclitaxel is a widely used chemotherapeutic agent indicated for the treatment of ovarian, breast, non-small cell lung carcinomas and Kaposi's sarcoma. Unfortunately, the dose-limiting side-effect of this highly efficacious antitumor drug is the precipitation of peripheral neuropathy accompanied by a chronic neuropathic pain syndrome that may resolve within weeks or months of drug termination, or it may last for years [7, 8]. The clinical management of these subjects is very difficult as current pain drugs are only marginally effective for treating the symptoms of CIPN, and they also display additional unacceptable side effects [9]. The tragedy here is that paclitaxel-evoked neuropathic pain is a leading cause of discontinuation of an otherwise successful therapy and paclitaxel doses are often restricted to levels that are suboptimal for killing tumor cells [7, 8]. The very same problem is seen in chemotherapeutics of other classes.
Chemotherapeutic strategies to treat various cancers are short-circuited by the numerous systemic side-effects observed. Pain, which is arguably the most debilitating and feared side-effect, greatly reduces the success of such strategies by limiting doses and imparting psychological distress. New methodologies to prevent or even reverse chemotherapy-induced chronic neuropathic pain would be transformative; indeed, the future development of a therapeutic of this nature is significant in two ways. First, the impact on quality of life for subjects would be enormous. The ability to reduce/eliminate CIPN amongst cancer survivors would result in lower costs related to the current chronic narcotic dependence needed to manage the pain. In addition, improved productivity in the work place would result, as many subjects with CIPN are unable to work and can no longer operate vehicles. Secondly, more lives may be saved. Subjects who currently would not be candidates for treatment (or continued treatment) with drugs such as paclitaxel due to the impending (or worsening) neuropathy, would instead benefit from full power anti-tumor dosages, if such dosages were to be made tolerable.